1. Field of the Invention
This invention pertains to a low temperature process for making 2-deoxy-2,2-difluoro-D-ribofuranosyl-1-.alpha.-sulfonates for use as intermediates in the preparation of known anti-neoplastic and anti-viral agents.
2. State of the Art
Fluorine substitution has been investigated extensively in drug research and biochemistry as a means of enhancing the biological activity and increasing the chemical or metabolic stability of nucleosides. The replacement of a hydrogen by fluorine in a bioactive molecule is expected to cause minimal steric pertubations with respect to the molecule's mode of binding to receptors or enzymes and aid in overcoming the chemical and enzymatic instability problems of nucleosides. Difluorodeoxynucleosides are typically synthesized by coupling a 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonate with a purine or pyrimidine nucleobase.
U.S. Pat. No. 4,526,988 describes a process for making a hydroxy-protected 1-methanesulfonyl-2-deoxy-2,2-difluoro-D-ribofuranosyl derivative by reacting 3,5-bis(t-butyldimethyl silyoxy) hydroxy protected 2-deoxy-2,2-difluoro-D-ribofuranose dissolved in dichloromethane with methanesulfonyl chloride, in an equimolar amount of a suitable acid scavenger such as triethylamine for 3 hours at about 25.degree. C. The resulting compound is coupled with a purine or pyrimidine base to form an anomeric mixture of nucleosides.
Pending U.S. patent application Ser. Nos. 07/902,302, Attorney Docket X-8406 and 07/902,312, Attorney Docket X-8236, both filed contemporaneously herewith, describe a stereoselective coupling process for preparing nucleosides which is believed to proceed via S.sub.N 2 displacement. In order to prepare beta-nucleosides via the S.sub.N 2 pathway, there is a need for a stereoselective process for preparing alpha-anomer enriched ribofuranosyl sulfonate intermediates for use in the synthesis of nucleosides.
Accordingly, one object of the present invention is to provide a stereoselective process for preparing alpha-anomer enriched ribofuranosyl sulfonates.
Another object of the present invention is to provide a stereoselective process for preparing alpha-anomer enriched ribofuranosyl sulfonates in yields higher than those previously achieved by conventional processes.